ANTI-HYPERTENSIVE DRUGS

ANTI-HYPERTENSIVE DRUGS: 

ANTI-HYPERTENSIVE DRUGS Dr. M. Khurram Mahmood Assistant Professor Pharmacology

HYPERTENSION: 

HYPERTENSION Current definition (W.H.O.) A level of systolic blood pressure of 140 mm Hg or above, or a level of diastolic blood pressure of 90mm Hg or above, by repeated measurements over periods of several weeks. It may be systolic or diastolic.

BP Scheme for Adults (in mm Hg) : 

BP Scheme for Adults (in mm Hg) Normal: Systolic BP <120 and Diastolic BP <80 Prehypertension: SBP 120-139 or DBP 80-89 Stage 1 hypertension: SBP 140-159 or DBP 90-99 Stage 2 hypertension: SBP 160 or DBP 100 Malignant Hypertension SBP 200 or more DBP 120 or more

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HYPERTENSION Prevalence Types & Etiology Treatment Non Pharmacological Pharmacological

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HYPERTENSION Most common cardiovascular disease - 28% of adult USA population Data from the National Health and Nutrition Examination Survey (NHANES) - 50 million or more Americans have high blood pressure (BP) warranting some form of treatment Worldwide prevalence - 1 billion individuals approximately 7.1 million deaths / year

HYPERTENSION: 

HYPERTENSION The World Health Organization reports that suboptimal BP (>115 mm Hg SBP) is responsible for 62% of Cerebrovascular disease and 49% of Ischemic heart disease, with little variation by sex. In addition, suboptimal blood pressure is the number one attributable risk for death throughout the world

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HYPERTENSION 95% cases – idiopathic - primary or essential Pathogenesis of primary hypertension - heterogenicity of complex series of cause viz. heredity, increased fluid volume, renal sodium transport deficiency, increased vascular tone and thickness, sympathetic nervous system hyperactivity (neurogenic hypertension), chronic stress, rennin-angiotensin system involvement, diminished vasodepressor hormones (prostaglandins) and miscellaneous like obesity, physical inactivity, excess or deficiency of minerals (potassium, magnesium) and alcohol.

HYPERTENSION: 

HYPERTENSION heredity, sodium, stress and obesity are proved to play an important role as causative factors In less than 5% of cases, it is secondary i.e. has some identifiable cause (renal, endocrine and neurological abnormalities, drug-induced and cardiovascular defects)

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HYPERTENSION Appropriately called SILENT KILLER Sustained arterial hypertension damages BVs in kidneys, heart & brain and leads to increased incidence of renal failure, coronary disease, cardiac failure and stroke Directly related to the extent of BP elevation

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First Line Of Defense - modify the risk factors associated with it heredity, age, race, or sex - can't do anything can lose weight, exercise more, stop smoking, and improve our eating habits. We may even be able to alter our personality Type-A personalities (the hard-driven, success-oriented types who start blowing their horns before the traffic light has changed) how to become easy-going, Type-B personalities .

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BP=CO x PVR Normal regulation of blood pressure Postural Baroreflex Renal Response to Decreased BP

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Regulation of Blood Pressure Baroreceptors & the sympathetic NS: for rapid moment to moment control Renal responses: Renin Angiotensin – Aldosteron system ---- for long term control. Others: Endothelin Nitric oxide Vasopressin

MONOTHERAPY VERSUS POLYPHARMACY: 

MONOTHERAPY VERSUS POLYPHARMACY

CLASSIFICATION – Main Groups : 

CLASSIFICATION – Main Groups DIURETICS SYMPATHOPLEGICS CALCIUM CHANNEL BLOCKERS DRUGS ACTING ON RENIN ANGIOTENSIN SYSTEM ACE INHIBITORS ANGIOTENSIN RECEPTOR BLOCKERS VASODILATORS

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A. DIURETICS Thiazides & related agents Hydrochlorothiazide Chlorthiazide Benzthiazide Chlorthalidone Indapamide Loop diuretics Furosemide Bumetanide Ethacrynic acid

Diuretics.. : 

Diuretics.. Potassium Sparing Diuretics Triamterene Spironolactone Amlioride

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B. SYMPATHOPLEGICS 1. Centrally acting drugs Methyldopa Clonidine Guanabenz Guanfacine 2. β -Adrenergic receptor antagonists Propranolol Metoprolol Atenolol

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SYMPATHOPLEGICS 3. α -Adrenergic receptor antagonists Prazosin Terazosin Doxazosin Phenoxybenzamine Phentolamine 4. Alpha & Beta Blockers Labetalol Carvedilol

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SYMPATHOPLEGICS 5. Adrenergic Neuron Blockers Guanethidine Reserpine 6. Ganglion Blocking Agents Trimetaphan

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C.  CALCIUM - CHANNEL BLOCKERS Dihydropyridines Nifedipine (Adalat) Nicardipine Nimodipine Amlodipine Nisoldipine Nitrendipine Felodipine Isradipine

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Phenylalkylamines Verapamil (Calan) Gallopamil Diphenylpiperazines Flunarizine Trimetazidine Ranolazine

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Benzothiazepines Diltiazem (Herbessor) Diarylaminopropylamine Bepridil Misc Cinnarizine Prenylamine

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D. DRUGS ACTING ON RENIN ANGIOTENSIN SYSTEM Angiotensin Converting Enzyme (ACE) Inhibitors Captopril Enalapril Lisinopril Benzapril Perindopril Quinapril Ramipril Trandolapril

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Angiotensin II Receptor Blockers (Competitive antagonists ) Losartan Valsartan Candesartan Eprosartan Irbesartan Telmisartan Saralasin

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E. VASODILATORS 1. Arterial Oral: Hydralazine Minoxidil Parenteral: Diazoxide Fenoldopam 2. Venodilators: Nitroglycerine 3. Aterial and Venous: Sodium Nitroprusside

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Drugs that alter sodium & Water Balance Dietary control of B.P by sodium restriction Preventive & Non toxic therapeutic measure

Diuretics: 

Diuretics M.O.A & Haemodynamic Effects  B.P by Primarily Because of Sodium Depletion Initially : Because of  Blood volume &  CO P.R may  After 6-8 Wks: CO Returns to Normal P.R  Sodium  B.V Stiffness & Neuronal Reactivity   P. Resistance Because of  Na+ & Ca++ Exchange

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Diuretics Reverse this. Some diuretics have direct vasodilator Activity - Indapamide Diuretic  B.P by 10-15mn Used alone in mild or moderate HTN Used in combination with sympathoplegics & vasodilators in more severe HTN (they counteract the compensatory mechanisms  Sodium Retention) TOXICITY – electrolyte & metabolic

Diuretics - Situations favouring: 

Diuretics - Situations favouring Elderly patients Low renin hypertension Isolated systolic hypertension Obese patients with volume overload Renal disease with Na + retention Low cost therapy

Diuretics To be avoided in: 

Diuretics To be avoided in Young active hypertensive Diabetes or family history of diabetes Gout or family history of gout Abnormal lipid profile Pregnancy induced hypertension

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B. SYMPATHOPLEGICS Moderate to severe hypertension, most effective when used concomitantly with a diuretic Classified acc to the site at which they impair the sympathetic reflex arc Can elicit compensatory effects through mechanisms not dependent on adrenergic NS (retention of Na + by the kidney)

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SYMPATHOPLEGICS 1. Centrally acting drugs Methyldopa Clonidine Guanabenz Guanfacine 2. β -Adrenergic receptor antagonists Propranolol Metoprolol Atenolol 3. α -Adrenergic receptor antagonists Prazosin Terazosin Doxazosin Phenoxybenzamine Phentolamine

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SYMPATHOPLEGICS 4. Alpha & Beta Blockers Labetalol Carvedilol 5. Adrenergic Neuron Blockers Guanethidine Reserpine 6. Ganglion Blocking Agents Trimetaphan

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Centrally acting sympathoplegic drugs These drugs are central α 2 receptor agonists. Reduce sympathetic out flow from vasomotor centers in the brain stem Allow these centers to retain or even increase their sensitivity to baroreceptors. Their effects are not dependent on posture The drugs are: Methyldopa Clonidine Guanabenz Guanfacine

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MOA - α - Methyldopa pro-drug , an analog of L - DOPA Taken up into the adrenergic nerve terminals by uptake -1 Metabolized to active metabolite α - methyl Nor-epinephrine ,like synthesis of Nor-epinephrine α - Methyldopa → α - Methyldopamine → α - methyl Nor-epinephrine ( α - Methyl NE) α - Methyl NE replaces Nor epinephrine in the vesicles.

MOA - α-Methyldopa…: 

MOA - α - Methyldopa… α - Methyl NE is released instead of NE & acts as agonist at post synaptic α 2 receptors in VMC in the brain stem . Inhibits adrenergic neuronal out flow from the brain stem to the peripheral sympathetic NS. Methyl Nor epinephrine ↓ Blood pressure mainly by↓ PVR , HR & CO variably ↓ Methyl NE is not a substrate for MAO like Nor epinephrine. At periphery α - Methyl NE acts as vasoconstrictor ,so it is not MOA as anti-hypertensive

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Evidence in favor of central sympathoplegic by acting as agonist at α 2 receptors: 1. Much lower doses are required to decrease blood pressure in animals if administered centrally by intraventricular Inj as compared to I/V. 2. α 2 Selective antagonists/ α antagonists administered centrally block the anti hypertensive effect of α - Methyldopa 3. Potent inhibitors of dopa -decarboxylase administered centrally block the anti hypertensive effect of α - Methyldopa ; indicating that metabolic conversion of pro-drug is required for its effect

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Therapeutic uses 1. Antihypertensive Widely used in the past for mild to moderate hypertension along with a diuretic. Now preferred drug in pregnancy, effective & safe for both mother & fetus. Valuable in hypertensives with renal insufficiency , no dosage adjustment required. In Hypertensive crisis ; may be given I/V.

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Adverse effects Sedation– the most common specially at onset of treatment. On long term use: Persistent lassitude & impaired mental concentration. Mental Depression , Nightmares , vertigo. Extrapyramidal symptoms-- Parkinsonian signs. Hyperprolactinemia--- lactation in males & females. Postural hypotension ; only in volume depleted patients Positive Coombs test in 10-20 % cases treated for longer than12 months.

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Adverse effects of clonidine Sedation –centrally mediated & dose dependent. Xerostomia (dry mouth) centrally mediated & dose dependent. Depression--- withdraw the drug. C/I in patients at risk of depression Hypertensive crisis on sudden withdrawal. Marked rise in blood pressure if drug is stopped abruptly.

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β -Adrenergic receptor antagonists i) Non-selective (  1 ,  2 ) blockers Propranolol , Pindolol , Nadolol, Carteolol , Penbutolol ii) Cardioselective (  1 ) blockers Acebutolol , Atenolol, Betaxolol , Bisoprolol , Esmolol, Nebivolol & Metoprolol iii) Both  &  blockers Labetalol & Carvedilol

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MOA of ↓ blood pressure: Due to β -blockade: a) ↓ CO b) Anti-renin effects c) Blockade of Presynaptic β receptors d) Central effects Postural hypotension is not prominent. Choice of β 1 selective / nonselective is individualized.

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Beta Blockers Mild to moderate hypertension In severe hypertension - in combination therapy with direct vasodilators to prevent compensatory tachycardia. In hypertensive emergencies (Labetalol , Esmolol) Intraoperative & Postoperative hypertension (Esmolol) Hypertension with chronic heart failure (Carvedilol , Metoprolol, Bisoprolol) Hypertension with pheochromocytoma use β - blockers after α blocker.

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Beta Blockers Suitable for patients of hypertension Low cost therapy. Young patient; less effective in elderly & blacks. Coexisting anxiety or tachycardia , Angina. Non-obese, high renin hypertensive. Post-MI patients Pregnancy (cardioselective & β blocker with ISA)

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Alpha-1 Blocker – Prazosin Highly selective for α 1 receptors , 1000 fold > α 2 Marked postural hypotension with first dose---- first dose phenomenon; so first dose given low& at bed time With selective α 1 blockers , less reflex tachycardia as negative feed back on NE release via presynaptic α 2 is not blocked. Relax smooth muscles of both resistance & capacitance BV  ↓ PVR & ↓ blood pressure . Blood pressure is reduced more in upright than in supine position.

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Retention of salt & water if used without a diuretic. More effective in combination with β blocker & diuretic. Relaxes smooth muscle in the prostate & bladder base  useful in coexisting urinary obstruction , improves urinary low. Adverse effects: Postural hypotension---first dose phenomenon. Fluid & water retention, risk of CHF, if used alone. Sedation, Nasal congestion, Diarrhea, failure of Ejaculation.

Adrenergic Neuron Blockers: 

Adrenergic Neuron Blockers These are a group of drugs which act on adrenergic nerve terminals and block their function / effect on the neuroeffector organs by either inhibiting the synthesis of noradrenaline or its storage or release in the adrenergic nerve terminals

Classification (Acc to MOA) : 

Classification (Acc to MOA) I. Drugs that Prevent Release of Noradrenaline Guanethidine Debrisoquin Bethanidine Guanoxan Guanadrel II. Drugs that Inhibit Storage of Noradrenaline Reserpine Deserpidine III. Drugs that Interfere with Synthesis of Nordrenaline Metyrosine (  Methyl tyrosine)

Adverse Effects: 

Adverse Effects Postural Hypotension Hypotension following exercise specially in high doses Generalized weakness Sodium & Fluid retention Diarrhoea Nasal congestion Delayed or retrograde ejaculation Heart failure (Limited cardiac reserve) Severe hypertensive reactions (Pheochromocytoma) Hypertensive crisis (with directly acting sympathomimetics)

GANGLION-BLOCKING DRUGS: 

GANGLION-BLOCKING DRUGS Prevent reflex changes in H.R elicited by vasoconstriction ( α 1) & vasodilation ( β 2). Do not prevent changes in H.R elicited directly by the drug ( β 1 & M2).

Introduction: 

Introduction Block the action of ACh and similar agonists at nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia. Ganglion-blocking drugs are important and used in pharmacologic and physiologic research because they can block all autonomic outflow. Lack of selectivity confers such a broad range of undesirable effects that they have limited clinical use.

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C.  CALCIUM - CHANNEL BLOCKERS Dihydropyridines Nifedipine (Adalat) Nicardipine Nimodipine Amlodipine Nisoldipine Nitrendipine Felodipine Isradipine Phenylalkylamines Verapamil (Calan) Gallopamil

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CALCIUM - CHANNEL BLOCKERS Diphenylpiperazines Flunarizine Trimetazidine Ranolazine Benzothiazepines Diltiazem (Herbessor) Diarylaminopropylamine Bepridil Misc Cinnarizine Prenylamine

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Type of Voltage-gated / Voltage-dependent Calcium Channels L Type Muscle Neurons Heart more sensitive to Verapamil T Type Neurons Heart N Type Neurons P Type Cerebellar purkinje neurons

Mechanism of Action in Blood Vessels: 

Mechanism of Action in Blood Vessels Blocking of voltage gated-calcium channels  Reduced Ca ++ in smooth muscle cells  Reduced formation of Ca ++ / Calmodulin complex  No activation of myosin light chain kinase  No Phosphorylation of myosin light chain No contraction  Vasodilatation  Decreased Peripheral Resistance Decreased BP

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ON HEART Blockade of voltage gated calcium channels  Reduced Ca ++ influx into cardiac cells  No breaking of troponin bridge  Less force & rate of contraction  Decreased BP

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Ph. Kinetics Nifedipine Complete oral absorption Peak plasma levels 20-45 Min Detectable plasma levels 6 Min D.O.A 8-12 hrs Orally active, almost complete absorption verapamil extensive P.P.B (80-90%) Diltiazem Elimination half life 3-6 hrs. Extensive metabolism in liver. Verapamil and Nifedipine excreted in urine Diltiazem excreted in faeces.

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Pharmacological Actions / Effects Group Actions On Heart Anti Anginal ( PVR & CO) Anti hypertensive( PVR & CO) Anti arrhythmic ( Verapamil & Diltiazem) Useful in Myocardial infarction ( O 2 requirements)

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Other Effects Anti-platelet effect (interfere with platelet aggregation) Effect on other smooth muscles (relaxation of bronchiolar, GIT and uterine sm. muscles) Action on Skeletal muscles (no effect) Decreased release of insulin - Verapamil Decrease secretion of exocrine glands – less effect because of difference of Ca channels Verapamil blocks reverse transporter p-170 glycoprotein

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THERAPEUTIC USES Hypertension Angina Supraventricular arrhythmias Hypertorophic cardiomyopathy Prevent increase in infarct size Migraine Prophylaxis Raynaud’s phenomenon Atherosclerosis Subarachnoid haemorrhage (Nimodipine)

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Toxicity (extension of therapeutic actions) Cardio-depression, AV blocks, Hypotension Bradycardia, Cardiac failure Minor AEs Constipation, Nausea Edema of dependent parts Skin rashes, Flushing, Dizziness

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DRUGS ACTING ON RENIN ANGIOTENSIN SYSTEM ACE INHIBITORS ANGIOTENSIN RECEPTOR BLOCKERS

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Angiotensin Converting Enzyme (ACE) Inhibitors Captopril Enalapril Lisinopril Benzapril Perindopril Quinapril Ramipril Trandolapril

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Angiotensin II Receptor Blockers (Competitive antagonists) Losartan Valsartan Candesartan Eprosartan Irbesartan Telmisartan Saralasin

MOA of ACE Inhibitors : 

MOA of ACE Inhibitors Renin is released from JGA Renin acts upon Angiotensinogen, to split off the inactive decapeptide Angiotensin I . Angiotensin I is then converted primarily by endothelial angiotensin converting enzyme(ACE) to Octapeptide, angiotensin II. Angiotensin II - most powerful vasoconstrictor. Also stimulates the synthesis and secretion of aldosterone which retains sodium & water. ACEIs inhibit the converting enzyme peptidyl dipeptidase & prevents formation of Angiotensin II. The same enzyme (under the name of plasma kininase) inactivates bradykinin, so it accumulates Bradykinin produces vasodilation directly as well as through ↑ PG synthesis.

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Actions of Angiotensin – II Generalized vasoconstriction, especially marked in efferent arterioles of the kidney. Is 40 times more powerful vasoconstrictor than NE. ↑ release of nor- epinephrine from sympathetic nerve terminals, reinforcing vasoconstriction & ↑ the rate and force of contraction of the heart Stimulation of proximal tubular re-absorption of Na + Stimulates secretion of aldosterone from the adrenal cortex which retains sodium & water . Cell growth (Mitogenesis) in the heart and in arteries.

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PHARMACOLOGICAL EFFECTS - Antihypertensive effect Due to inhibitory action on the Renin - Angiotensin System Decreased Angiotensin II less vasoconstriction, hence Vasodilatation Decreased PR . Due to increased bradykinin Bradykinin degradation is prevented, accumulation of bradykinin – a potent vasodilator So  B.P principally by  P.R. CO & H.R. not significantly changed No reflex tachycardia (Safe in patients ē I.H.D) due to • Downward resetting of baroreceptors OR •  Parasympathetic activity. Effective in Patients ē High & Normal Renin Levels

PHARMACOLOGICAL EFFECTS…: 

PHARMACOLOGICAL EFFECTS… Effect on Nephropathy in D.M.  Proteinuria Stabilize Renal Function. Improve intra renal hemodynamics Effect on Heart Useful in C.C.F  After Load & Preload. Useful after Myocardial Infarction  Post Myocardial Infarction Remodeling Even in the absence of lowering of BP

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Pharmacokinetics Mostly prodrugs, Orally active Absorption : Rapid from GIT (B.A=70%)  B.A ē food Metabolism : Conjugation in liver Distribution : Well but not to C.N.S Excretion : Kidneys except fosinopril & moexipril Pro -drugs to active drugs by hydrolysis in Liver. Enalapril Deesterified  Enalaprilat – t ½ 11 hrs Most of ACEIs excreted by kidneys so dosage should be  in renal insufficiency.

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Adverse Effects Altered Taste Allergic Skin Rashes 10% cases, less with newer long acting drugs Drug Fever Marked Hypotension ē First Dose in hypovolaemic patients Acute Renal Failure In Renal Artery Stenosis Hyperkalemia (more likely in renal insufficiency & diabetic pts) Dry-cough, sometimes with wheezing because of  Bradykinin Angioedema because of  Bradykinin Neutropenia serious but rare, in Autoimmune diseases Proteinuria In Renal insufficiency ē High Doses of Captopril . Teratogenc Effects In 2nd & 3rd Trimester; Fetal Hypotension, Anuria & Renal Failure, Sometimes Fetal malformations/Death – CI in pregnancy

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Drug Interactions With K + Supplements /K + Sparing Diuretics (Marked hyperkalemia) Non Steroidal Anti. Inflammatory Drugs may impair the hypotensive effect which is mediated through Bradykinin Contraindications Pregnancy Therapeutic Uses Hypertension -with a thiazide diuretic or beta blockers Congestive Cardiac Failure Diabetic Nephropathy Myocardial Infarction

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Angiotensin II type I (AT 1 )Receptor Blockers (Competitive antagonists) Peptide Antagonists: Saralasin Non-Peptide Antagonists: Losartan , Valsartan Candesartan , Eprosartan Irbesartan , Telmisartan

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Angiotensin-II Receptor Blockers Two types: AT 1 & AT 2 1. AT 1 : Location predominate in vascular smooth muscles. Group G protein coupled. Effector Phospholipase C Second messenger IP 3 & DAG. Response Smooth muscle contraction within seconds

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2. AT 2 Location in all tissues in fetus In adults adrenal medulla, reproductive tissues, vascular endothelium & parts of the brain. Group G protein coupled. Effector Phospholipase A 2 , nitric oxide Second messenger cGMP. Functions Fetal tissue development Inhibition of growth & proliferation Cell differentiation Apoptosis Possibly vasodilation.

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M.O.A- Angiotensin-II Receptor Blockers Competitive Blockers of Angiotensin – II AT 1 Receptors So effects like ACEIs, with following differences: No Effect on Bradykinin , so no dry cough and no angioedema More effective than ACEIs (Angiotensin - II also generated by other Enzymes. Prolonged treatment disinhibits renin secretion & ↑ angiotensin-II levels → ↑ stimulation of AT 2 Producing vasodilatation and other beneficial effects. Adverse Effects: Like ACEIs except Dry cough & Angioedema

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Saralasin- Angiotensin Receptor Blockers… Also has weak agonistic activity. Useful tool for research Given by IV infusion. Not used as anti H.T other drugs are used

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VASODILATOR DRUGS Drugs that dilate B.Vs by acting directly on smooth muscles through non autonomic mechanisms Arterial vasodilators Hydralazine, Minoxidil, Diazoxide, Fenoldopam Arterial & Venous vasodilator Sodium Nitroprosside Venous Nitroglycerine Calcium Channel Blockers

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All drugs relax arteriolar SM ↓ PVR & ↓ blood pressure Sodium Nitroprusside also relaxes veins The hypotensive effect elicits compensatory responses Because sympathetic reflexes are intact orthostatic hypertension or sexual dysfunction does not occur VASODILATOR DRUGS…

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COMPENSATORY RESPONSES TO VASODILATOR DRUGS & BASIS FOR COMBINATION THERAPY

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↑ sympathetic out flow & ↑ rennin release ↑ HR. & Cardiac contractility-------- Increased CO--- ↑ blood pressure Vasoconstriction--- ↑ PR-- ↑ blood pressure ↑ renin ------ ↑ Angiotensin –II ----Vasoconstriction--- ↑ PR-- ↑ blood pressure & ↑ Aldosterone---- ↓ renal sodium excretion-- ↑ plasma volume---- ↑ blood pressure So vasodilators are used in combination therapy with Diuretics &  Blockers

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HYDRALAZINE Oral vasodilator Hydrazine derivative MOA Direct arteriolar dilator Do not dilate veins MOA not clear it probably acts through release of nitric oxide from endothelium

HYDRALAZINE…: 

HYDRALAZINE… Ph.k Well abs from GIT Rapid first pass metabolism in liver low B.A (25%) Metabolized by Acetylation - Slow or Rapid Acetylators due to genetic factors Rapid Acetylators  Greater First pass metabolism less B.A Slow Acetylators  Less First pass metabolism more B.A. Half Life : 2 - 4 hrs.

HYDRALAZINE…: 

HYDRALAZINE… Ph. Effects Arteriolar dilatation leads to decreased peripheral resistance & hence decreases blood pressure. Postural hypotension - uncommon. Hypotensive effect elicits compensatory responses Vasodilatation  Hypotension which causes : Increased sympathetic out flow & increased rennin release . Increased HR & contractility-------- Increased CO Increased PR----- Increased BP Increased Renin ------Increased Angiotensinogen---- Increased Aldosterone----Decreased renal sodium excretion------Increased plasma volume----- Increased BP

HYDRALAZINE…: 

HYDRALAZINE… Therapeutic uses Anti-hypertensive – in pregnancy for short term Rx, in severe cases in combination In CCF – decrease after load Toxicity Headache, Nausea, anorexia, sweating & flushing Palpitation, Dizziness Angina / arrhythmias (in Pt. ē I.H.D) Syndrome like Systemic Lupus Erythematosis in slow acetylators ( reversible) / in high doses With high doses - Arthralgia, Myalgia, Skin rashes, Fever Rare side effects: Peripheral Neuropathy, Drug fever.

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MINOXIDIL - Oral Arteriolar vasodilator MOA Pro drug, converted to Minoxidil sulphate, an active metabolite which is K + channel opener. This action stabilizes the membrane at its RMP, and makes contraction less likely & hence relaxation of vascular smooth vasodilatation Decreased PR Decreased BP Compensatory responses are elicited, so combined with Diuretic or a Beta blocker.

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Ph. Kinetics Well absorbed from GIT, BA:90% Metabolized by conjugation DOA: 24 Hrs Only given orally Toxicity Tachycardia, palpitations, angina Edema---When doses of beta blockers & diuretics are inadequate. Headache, sweating & hirsuitism (Topically used for baldness) MINOXIDIL…

MINOXIDIL…: 

MINOXIDIL… Therapeutic uses In severe hypertension in combination therapy Topically for baldness

Sodium Nitroprusside: 

Sodium Nitroprusside Complex of Iron, Cyanide, Nitroso Group

Sodium Nitroprusside..: 

Sodium Nitroprusside.. Powerful parenteral vasodilator of Arterioles & Veins Given by I/V infusion – t ½ = few min OOA: within Seconds DOA: brief 1-10 min Rapidly metabolized by uptake in to RBCs with liberation of cyanide Cyanide metabolised to thiocynate in presence of sulphur donor by mitochondrial enzyme (rhodanase) Thiocynates excreted by kidneys slowly

Sodium Nitroprusside..: 

Sodium Nitroprusside.. M.O.A Activate guanylyl cyclase, either via release of nitric oxide or by direct stimulation of the enzyme.  Increase intracellular cGMP,  Relaxation of S.M of Arterioles + Veins  Vasodlatation   P.R   B.P

Sodium Nitroprusside..: 

Sodium Nitroprusside.. Ph. Effects Rapid  in B.P, In Supine position & Upright position, more marked in upright position. Effect disappears within 1-10min on stopping infusion Hypotension is due to decreased PR, C.O- normally no change / slight   C.O – In CCF & Low C.O. Because Of:  After Load.  Preload.

Sodium Nitroprusside..: 

Sodium Nitroprusside.. AEs Excessive hypotension. Palpitation Nausea, vomiting, perspiration. AEs due to Cyanide Toxicity Metabolic Acidosis Arrhythmias Excessive hypotension Death Prevented By Soduim Thiosulphate or Hydroxycobolamine

Sodium Nitroprusside..: 

Sodium Nitroprusside.. AEs because Of thiocyanate Weakness, Disorientation, Psychosis, Muscle Spasm & convulsions Delayed Hypothyroidism Methemoglobinaemia during infusion may occur

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DIAZOXIDE Long Acting arteriolar vasodilator MOA Prevents Vascular Sm. muscle contraction by opening ATPase sensitive K + Channel  Stabilization of Membrane Potential at RMP  No Contraction Relaxation   P.R   B.P

DIAZOXIDE…: 

DIAZOXIDE… Ph. Effects dilates only Arterioles   P.R & Rapid  in B.P  H.R   C.O (Compensatory Mechanism) Ph.K Given I/V, bound To P.Proteins & Vascular Tissue Exc - 30% unchanged, 70% Metabolites

DIAZOXIDE: 

DIAZOXIDE Ad. Effects • Excessive Hypotension – stroke & MI, the reflex sympathetic response can provoke angina • Salt & Water retension • Hyperglycemia - Secretion of insulin from  -cells is inhibited Th. Uses Hypertension – Severe With  Blocker / Diuretics In Insulinoma to treat Hypoglycaemia

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FENOLDOPAM Recently discovered peripheral arteriolar dilator Racemic mixture, R isomer is Pharmacologically active. MOA Acts primarily as an agonist of dopamine D1 receptors, resulting in dilatation of peripheral arteries & natriuresis

Pharmacokinetics - FENOLDOPAM : 

Rapid metabolism by conjugation Half-life: 10 min – given by continues IV infusion Initiated at low dose (0.1 mcg/kg/min) Titrated upward every 15-20 min to a max dose of 1.6 mcg/kg/min until the desired BP reduction is achieved Pharmacokinetics - FENOLDOPAM

FENOLDOPAM…: 

FENOLDOPAM… Th. Uses Used for hypertensive emergencies and postoperative hypertension - Given by intravenous infusion AEs Major toxicities are reflex tachycardia, headache, flushing. & even hypokalemia may occur Increase in IOP. --- C/I in glaucoma

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TREATMENT OF HYPERTENSIVE EMERGENCIES ( Hypertensive Crisis / Malignant hypertension) An emergency condition resulting from untreated primary hypertension – can prove lethal if not managed in time B.P. 200/120 mm Hg. If not treated - Cerebral Haemorrhage - Epistaxis - Acute Heart Failure - Retinal Haemorrhages

TREATMENT OF HYPERTENSIVE EMERGENCIES….: 

TREATMENT OF HYPERTENSIVE EMERGENCIES…. Pt. is monitored in an intensive care unit with continuous recording of arterial B.P. Fluid in-take & out-put monitoring. Daily measurement of body weight.

TREATMENT OF HYPERTENSIVE EMERGENCIES…: 

TREATMENT OF HYPERTENSIVE EMERGENCIES… Anti H.T Drugs Used I/V Sodium Nitroprusside/fenoldopan as infusion. Nifedipine sublingually Methyl Dopa I/V ACE inhibitors (Captopril). Hydralazine orally Prazosin (  Blockers) &  - Blockers - orally Labetalol orally Diuretics to prevent volume expansion - Furosemide is the drug of choice. Dialysis may be a necessary alternative to the loop diuretics in patients with oliguric renal failure. Clonidine is contraindicated .

TREATMENT OF HYPERTENSIVE EMERGENCIES…: 

The Diastolic B.P should not be normalized but kept at 100-110mmHg in first few hours to prevent cerebral Hypoperfusion, Brain injury. Because chronic hypertension is associated ē Auto regulatory changes in cerebral Blood Flow. Subsequently B.P. is normalized by Oral Antihypertensive drugs over several Weeks. TREATMENT OF HYPERTENSIVE EMERGENCIES…

Outpatient therapy of hypertension: 

Non-pharmacological management salt restriction , wt. reduction , exercise , ↓ stress , ↓ alcohol Pharmacological management Outpatient therapy of hypertension

Mono / single drug therapy: 

Mono / single drug therapy desirable because Better compliance Cost effective Generally A/E are fewer – no drug interactions Thiazide diuretics, β blockers, ACEIs, AT 1 blockers & Ca ++ channel blockers ----- all reduce the complication of hypertension

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Rationale of Combination therapy / Polypharmacy To eliminate compensatory responses Vasodilators with diuretics & β blockers. Inadequate responsiveness to one drug: 2 nd drug with different MOA is added Some patients may require a 3 rd drug.

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Patient’s compliance: Generally hypertensive patients are asymptomatic so compliance is poor due to A/E of drugs. To improve compliance : Individualize choice of the drug. Educate patient regarding the disease / complication & drug . Dosing regimens should be simplified. Advise monitoring of blood pressure at home.

The Essential Points of JNC 7: 

The Essential Points of JNC 7 For patients age 50 or older, elevated SBP is a stronger cardiovascular risk factor than elevated DBP. Within the BP range of 115/75 mm Hg to 185/115 mm Hg, each increment of 20/10 mm Hg doubles cardiovascular risk. Prehypertension warrants management with lifestyle modification (e.g., low-salt diet, regular physical activity). For patients with hypertension, the basic BP-control target is <140/<90 mm Hg, but the target is <130/<80 mm Hg for patients with diabetes or renal disease.

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Thiazide diuretics are recommended as initial therapy for uncomplicated hypertension, either alone or in combination with other agents. This recommendation is supported by an accompanying meta-analysis of 42 clinical trials (192,478 participants) done by researchers who were independent of the guideline authors; the meta-analysis showed that low-dose diuretics were significantly better than placebo for preventing coronary heart disease, heart failure, stroke, and all-cause mortality. No other drug class was significantly better than low-dose diuretics for preventing these outcomes. Most hypertensive patients will require 2 or more medications to achieve BP goals. When initial BP is more than 20/10 mm Hg above goal, clinicians should consider initiating therapy with 2 agents, usually including a diuretic. The authors emphasize the importance of the physician-patient relationship and patient motivation in fostering treatment adherence.